Limb Girdle Muscular Dystrophies (LGMD) are a heterogeneous group of inherited neuromuscular diseases, defined by progressive muscle weakness and atrophy. They are characterized by a progressive dystrophic pattern involving limb-girdle muscles.
Mutations in DYSF gene are responsible for a wide range of phenotypes characterized by the absence of dysferlin in skeletal muscle and an autosomal recessive mode of inheritance. So far, three main phenotypes have been reported: Miyoshi Myopathy (MM), Limb Girdle Muscular Dystrophy type 2B (LGMD 2B), and Distal Myopathy with Anterior Tibial onset (DMAT).
The objectives of this work were:
• To study the DYSF gene in patients from Spanish population, not previously analysed in this population.
o To design a technical strategy to analyse the DYSF gene
o To optimize the diagnostic process using RNA vs DNA
• To analyse gene rearrangements (deletions or duplications).
• To characterize the mutational spectrum in our population
• To establish a genotype-phenotype relationship
• To analyse possible modifiers genes
Results from this work had been published:
-Abnormal expresión of dysferlin in skeletal muscle and monocytes supports primary dysferlinopathy in patients with one mutated allele.
M.Meznaric, L. González-Quereda, E. Gallardo, N. de Luna, P. Gallano, M. Fanin, C. Angelini, B. Peterlin and J. Zidar.
European Journal of Neurology 2010. Article first published online: 18 OCT 2010 DOI: 10.1111/j.1468-1331.2010.03240.x
-A new phenotype of dysferlinopathy with congenital onset.
Paradas C, González-Quereda L, de Luna N, Gallardo E, García-Consuegra I, Gómez H, Cabello A, Illa I, Gallano P.
*Authors Paradas C and González-Quereda L contributed equally to this work.
Neuromuscul Disord. 2009 Jan;19(1):21-5. Epub 2008 Dec 11.
doi:10.1016/j.nmd.2008.09.015
This thesis drew the conclusions:
• It is possible to perform the mutational analysis in RNA isolated from total peripheral blood monocytes, avoiding the invasive method of muscle biopsy.
• DYSF gene shows high mutational heterogeneity in patients from Spanish population suffering from Limb Girdle Muscular Dystrophy type 2B and Miyoshi Myopathy.
• It is not possible to establish a genotype-phenotype correlation in dysferlinopathy patients.
• DYSF c.3191_3196dup is the most prevalent mutation in Spanish population.
• Patients from our population show high mutational heterogeneity and it is not possible to identify hotspots as mutations are expanded over the whole sequence of the gene.
• The DYSF gene study in mRNA vs genomic DNA allows:
o To establish a molecular diagnostic in a quick and efficient way.
o To detect a high number of mutations
o To detect all mutations changing the splicing process.
• Mutations in MG53 have not been identified in our serie of patients, so that, MG53 can not be considered as a modifier gene to date.
• It has been described a new phenotype of dysferlinopathy with congenital onset. This new phenotype widens the clinical spectrum of dysferlinopathies and add new data to the natural story of the disease.